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MeperidineFentanylSufentanilAlfentanilRemifentanilReceptorMuKappa Selective Mu receptor agonist Structure Phenylpiperidine derivative Phenylpiperidine derivativeAnalogue of fentanyl Potency 5-10 > fentanyl Greater receptor affinity**most potent** Analogue of fentanyl 1/5 – 1/10 potency of fentanyl Structurally unique – ester linkage susceptible to hydrolysis by non-specific plasma and tissue esterases**fastest elimination** Potency = fentanyl Clinical Use Post op painPost op shiveringPrimarily for labor pain AnalgesiaAdjunct to IABlunt circulatory response:Laryngoscopy Sudden change in surg. stimulation AnalgesiaInductionHeart room Blunt response to brief single stimulus:IntubationRetrobulbar blockIntubation dose = 15 mcg/kgBlunt circ response to high Des. = 10-20 mcg/kgBlunt catechol = 30 mcg/kgBlunt response to brief single stimulusInduction dose= 1 mcg/kgAnalgesic infusion during GA = 0.05 – 2.0 mcg/kg/min Need long acting opioids before infusion is stopped**Potency from least to greatest: Demerol < Morphine<Alfentanil <Fentanyl = Remifentanil < Sufentanil**Pharmacokinetics1/10th as potent as morphine100 mg = 10 mg morphineOnset IV = 10 minDOA = 2-4 hrsSimilar to atropine and possesses some antispasmodic qualities75x more potent that MSO4Onset = 30 sec Effect-site equil time = 6.8 minShort DOA d/t rapid redistribution to inactive tissue sites>potency and rapid onset d/t > lipid solubilityLungs = large inactive storage site,1st pass Pulm uptake – 75% of initial doseE1/2 x > than any other opioid; context sensitive ? x increases w/durationLonger E1/2 x in ElderlyHighly Protein bound 79-97%Large Vd12xs more potent than fentanylSufenta 5mcg = Fent 50 mcgRapid redistribution to inactive tissue sitesHigh tissue affinity d/t > lipid solubilityEffect-site equil time = 6.2 min1st pass pulm uptake = 60%Longer E ? x in Elderly & obeseHighly protein bound 92.5%Small VdAlfentanil 500 mcg = Fentanyl50 mcg = Sufentanil 5 mcgOnset = rapid; redistributes to inactive tissue sitesHighly non-ionized at physiological pHEffect-site equil time =1.4 minRenal Fail. Does not alter E ? x or clearanceShort E ? x = 1.5 hrsLonger E ? x w/CirrhosisHighly protein bound 92%Small Vd = low lipid solFastest elimination d/t rapid metabolism by blood non-spec. esterasesAccumulates less than other opioidsEffect site equil time = 1.1 minE ? x = 6 minSmall VdMeperidineFentanylSufentanilAlfentanilRemifentanilMetabolismExtensive Hepatic metabolism90% demethylated to active metabolite NormeperidineNormeperidine-hydrolyzed to an acid and excreted in urineNormeperidine E ? x = 15 hrs*Seizure Activity*E ? x of Meperidine = 3-5 hrs60% Protein BoundUse Cautiously in Elderly and Renal DiseaseExtensively Metabolized by:N-demethylationInactive metabolite = norfentanylExcreted by kidneysDetected in urine 72 hrs after single doseRapidly metabolized by:N-dealkylationO-demethylationInactive and active metabolites formed<1% unchanged in urineHigh lipid solubility -> max renal tubular reabsorptionClearance sensitive to hepatic blood flow2 independent Pathways:Noralfentanil major metaboliteEfficiently cleared by liver metabolism within 60 minRedistributes to inactive tissue sitesUnique among the opioids – rapid metabolismNot affected by Pseudocholinesterase DeficiencyCan be used in renal and hepatic diseaseSide EffectsCauses Histamine ReleaseOrthostatic ↓ BP ↑ HR and Mydriasis- modest atropine like effect↓ Myocardial contractility w/large dosesDelirium and Seizures***Life threatening interaction w/MAOIs = Serotonin Syndome***Type I Rxn:HypertensionAgitationSkeletal Muscle RigidityHeadacheHyperpyrexiaType II Reaction:HypotensionRespiratory DepressionComaNo Histamine releaseMarked BradycardiaPossible seizure activityChest wall and skeletal muscle rigidityItchy noseNo Histamine releaseHypotensionBradycardiaNo Histamine releaseHypotensionBradycardiaNo Histamine releaseHypotensionBradycardiaAcute Opioid toleranceSkeletal muscle rigidity with large dosesCodeineHydromorphoneMethadoneHeroinStructureMade from MorphineDerivative of MorphineSynthetic Opioid with prolonged duration of action (24 hrs)Synthetic Opioid produced by Acetylation of Morphine= DiacetylmorphinePharmacokineticsE ? x with PO = 3.5 hrsOnset IV almost immediatePeak = 5 – 20 minDOA = 2-5 hours5x as potent as Morphine2 mg = 10 mg MorphineE ? x = 35 hrsRapid penetration into the brain UsesEffective antitussive at 15 mg POSame as morphineGood for mod to severe painHeroin addictionSide EffectsHistamine Release with IV dosingNo histamine releaseSame SE as morphineSimilar SE to morphineLack nauseaGreat potention for physical dependencyMetabolismLimited 1st pass hepatic metabolism – effective when given PODemethylated to:Morphine and NorcodeineShorter DOA than morphine 4-5 hoursMetabolized in Liver to inactive metabolitesHydrolyzed in brain to active metabolitesOpioid Agonists-Antagonists drugs Pentazocine (Talwin)Butorphanol (Stadol)Nalbuphine (Nubain)Buprenorphine (Buprenex)receptorBind to MU receptors and act as a partial Agonist OR Antagonist effectsProvide weaker analgesia than opioid agonists – good for mild – moderate painProduce analgesia without respiratory depression side effects Antagonist quality creates a “CEILING” effect for analgesia (only first dose effective)Low potential for physical dependence Side effects similar to Opioids May cause Dysphoric Reactions Opioid Agonists-Antagonists Pentazocine (Talwin)Butorphanol (Stadol)Nalbuphine (Nubain )Buprenorphine (Buprenex)moa Opioid agonist Weak antagonist Similar to Pentazocine Related toOxymorphone Naloxone Derived from Opioid Alkaloid:Thebainereceptors Delta KappaMU low affinity Kappa moderate affinitySigma minimal affinity MU Antagonist effectsMU high affinity 50x > MSO4Slow dissociation = action Resistant to Antagonism of Naloxone (Narcan)effects Agonist effects Antagonized by Naloxone (Narcan)Antagonist effects Withdrawal Agonist effects 20 x > than PentazocineAntagonist effects 10 - 30 times greaterEqual potency Analgesia to MSO4 Analgesia Onset and DurationSimilar to Morphine (MSO4)Nubain 10mg IMVery Potent 0.3mg IM = 10mg Morphine usesTreatment of:Chronic Pain Relieves Moderate Pain Good for:Acute Pain rather than Chronic 10-20mg IV reverses the respiratory depression of Fentanyl postopBut maintains Analgesia Good for:Moderate to Severe PaindoseDose 10-30mg IV or 50mg PO50mg PO = 60mg Codeine Available in parenteral form 2 -3 mg IM = 10mg Morphine > 30mg “CEILING EFFECT” d/t antagonist activity pharm.kineticsandmetabolismExtensive 1st-Pass Hepatic Metabolism Metabolized to an inactive metabolite Excreted in Urine E ? x = 2- 3 hours Hepatic metabolism to inactive metabolitesExcreted in Urine E ? x = 2.5 - 3.5 hours Rapidly &Completely absorbed after IMMetabolized in the Liver Morphine-like Drugs Inactive E ? x = 3 - 6 hours Onset = 30 minDuration 8-10 hours Highly Lipid Soluble side effects Sedation Diaphoresis Dizziness Dysphoria Crosses the Placenta Fetal Depression Catecholamines HR BP PAP LVEDPSedation Diaphoresis Nausea Respiratory Depression Attenuates Opioid Agonist Activity**Abuse potential LOWDoes NOT cause HR BP PAPDrowsiness Incidences of Pulmonary EdemaNausea/Vomiting Respiratory Depression Opioid Antagonists structure Minor changes in structure of Opioid Agonist changes the Drug to an ANTAGONISTSubstitute an Alkyl Group for a Methyl Group receptorDisplaces Opioid agonist from the MU receptorsPure Antagonist DOES NOT activate the receptor Antagonism Naloxone (Narcan)receptorANTAGONIZES Mu Receptors ***pharm.kineticsShort Duration of Action = 30 - 45 mindose1 - 4mcg/kg Reverses Opioid-induced Respiratory Depression and Analgesia To avoid abrupt reversal of analgesia give 40 mcg (0.1 mL)uses Detect suspected physical dependence Used as continuous infusion to prevent respiratory depression and itching from neuraxial opioidsNeonatal Depression - Given at Delivery (this is with moms that are NOT addicts)Opioid-Induced Depression of Ventilation Treatment of deliberate opioid overdose metabolism Metabolized in the liver E ? x = 60 -90 minutes side effectsSide effects are due to reversal of analgesia and sudden perception of pain:Nausea / Vomiting Increased SNS activity Tachycardia Pulmonary Edema HTN Cardiac Arrhythmias (VF)Crosses Placenta Acute Withdrawal of neonate of Opioid-Dependent mom (can lead to baby’s demise) ................
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